tbuckley/cabot-search huggingface dataset:
Abstract 12567: A Novel Mouse Model Replicates Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia
Authors: Katharina Schimmel, Kenzo Ichimura, Adam Andruska, Edda F Spiekerkoetter
Journal: Circulation (2023)

Background: 1 in 5,000 people worldwide present with Hereditary Hemorrhagic Telangiectasia (HHT), a vascular disorder that is most frequently caused by mono-allelic loss of function either of the gene ALK1, or ENG . Up to 50% of patients with HHT develop Pulmonary Arteriovenous Malformations (pAVMs), abnormal connections between arteries and veins. Health consequences include stroke, or rupture of the pAVM with life threatening bleedings. How pAVMs develop is unknown and there is no cure. Aims: We here aim at generating the first mouse model with pAVMs in HHT to address how pAVMs arise and grow, and to enable preclinical drug testing. Our goal is to produce the characteristic sac-like appearance of pAVMs in random locations of the lung by replicating probable underlying genetic events of HHT patients. Methods and Results: pAVMs occur in a focal fashion, despite a systemic mono-allelic loss of function in either one of the genes ALK1 or ENG in HHT. Recently, somatic mutations causing a local bi-allelic loss of ALK1 or ENG were identified in skin vascular abnormalities of HHT patients, most likely in clonally expanding endothelial cells (ECs). To recapitulate this locally confined complete loss of function of Alk1 in the mouse lung, we generated a tamoxifen-inducible (TM) Cre-lox mouse in which bi-allelic deletion of Alk1 can be induced only in a subset of ECs of mouse pulmonary capillaries. TM was administered in P11 or P13 old mice. 5-6 days post-injection, focal sac-like structures of the pulmonary arteries with potential connections to veins were visible in random locations of the mouse lungs of Alk1 mutants, but not control lungs. Conclusion: Bi-allelic deletion of Alk1 in ECs of mouse pulmonary general capillaries closely mimics a local loss of function somatic mutation in the single functional allele of ALK1 , as uncovered in vascular abnormalities of patients with HHT. Our novel mouse model is the first to faithfully recapitulate the focal and sporadic occurrence of pAVM-like structures seen in HHT patients. This will now enable us to identify molecular drivers of pAVM formation and test therapeutics to prevent or halt pAVM development.
Abstract 16915: Considerations in Management of Cocaine-Induced Coronary Disease and Embolism
Authors: Tyler Huffaker, Anum Asif, Ahmed Almomani
Journal: Circulation (2023)

Background: Coronary embolism accounts for ~3% of cases of myocardial infarction (MI). We describe a case of a young patient with cocaine abuse with coronary thrombus resulting in acute coronary syndrome (ACS). Case: 33-year-old male with no known medical history seen in the ER with one hour of typical chest pain. EKG showed ST-segment elevations in inferior leads. Coronary angiogram demonstrated a hazy filling defect in the distal RCA as well as a 100% thrombotic occlusion of the right posterolateral branch of RCA likely due to distal embolization. Aspiration thrombectomy was performed with no residual stenosis. All other vessels were angiographically normal. Decision-Making: Our patient had no traditional coronary artery disease risk factors. Work-up for other coronary embolism causes and genetic thrombophilia was negative. We aspirated the thrombi rather than stenting, as stent thrombosis risk is &gt;10-fold in cocaine users in absence of any residual stenosis. Dual antiplatelet therapy was initiated given ACS presentation. Conclusion: Acute coronary thrombosis is a life-threatening complication of cocaine abuse. In lack of residual stenosis post-aspiration thrombectomy, stenting can be avoided due to high stent thrombosis risk in this patient population.
Abstract 19184: Depression Mediates the Relationship Between Physical Activity and Quality of Life Among Patients With Coronary Heart Disease
Authors: rochelle G szuba, Thomas Hoffmann, Mary Whooley, Abdelaziz Elnaggar, Mijung Park, Julene Johnson, Linda G Park
Journal: Circulation (2023)

Background: Depression, a known comorbidity in coronary heart disease (CHD), is associated with adverse cardiac events, mortality, symptom burden, physical limitation, and poor quality of life (QOL). Evidence has shown that depression impedes self-care behaviors including, physical activity. Similarly, regular physical activity has been shown to lessen depressive symptoms and improve cardiovascular health. However, there is limited research to determine whether depressive symptoms mediate or moderate the association between physical activity and overall QOL in the older adult population living with chronic CHD. Hypothesis: Depression mediates the positive association between physical activity and QOL. Depression is a moderator of physical activity and QOL. Objectives: 1) To determine the direct effect of depressive symptoms on physical activity and QOL; 2) to investigate the mediating effect of physical activity and depressive symptoms on QOL; and 3) to test the moderating effect of depressive symptoms on physical activity and QOL. Methods: This cross-sectional study collected 20-year follow-up survey data from 126 survivors from the Heart and Soul prospective cohort study of people living with CHD. Mediation testing was conducted using the steps described by Baron and Kenny. Results: Physical activity significantly predicted QOL ( β =.133, p =.02) and significantly predicted depressive symptoms ( β =-.1918, p =.0002); depressive symptoms significantly predicted QOL( β =-0.762, p &lt;.0001). After depression was added to the model, the relationship between physical activity and QOL was no longer significant, indicating a mediating effect. The average causal mediation effect was statistically significant (.1463, p =.0002). Depression was not a moderator of physical activity and QOL (p&gt;.05). Conclusions: This study demonstrated that depression mediated the effect of physical activity on QOL. The findings underscore the importance of addressing physical activity and depressive symptoms in interventions to improve the overall well-being and quality of life of individuals living with chronic CHD.
Abstract 13808: Investigating Autophagy in Experimental Autoimmune Myocarditis Using Single Cell RNA Sequencing and Spatial Transcriptomics
Authors: Monika Stefanska, Magdalena Bielawska, Karolina Tkacz, Katarzyna Sarad, Daria Krzysztofik, Kazimierz Weglarczyk, Maciej Siedlar, Gabriela Kania, Przemyslaw Blyszczuk
Journal: Circulation (2023)

Background: Autophagy has emerged as an important process in the context of heart failure. Experimental autoimmune myocarditis (EAM) represents an animal model of acute myocarditis (d19) and post-inflammatory dilated cardiomyopathy (d35). Aim: To explore autophagy dynamics in a mouse model of EAM at the single cell level. Methods: 6-8-week-old BALB/c mice were immunized with αMyHC peptide and complete Freund’s adjuvant. Single-cell RNA (scRNA) libraries were prepared using 10x Genomics technology and sequenced, targeting 50’000 reads/cell. For spatial transcriptomics, snap-frozen hearts embedded in OTC were sectioned into 10 μm-thick fragments and placed on 10x Genomics Visium Gene Expression Slide and processed using 10x Genomics Visium protocols. The data were analyzed using RStudio software. LC3B and Beclin-1 proteins were detected by IHC. Results: After quality control check, we included in the RNAseq analysis 25’058 cells clustering in 11 distinct cell populations (Fig. 1A). Expression of autophagic genes Atg7 and Becn1 was relatively consistent across all cell populations, whereas Atg3 and Map1lc3b (encoding LC3B) showed high expression specifically in monocytes. Analysis of monocytes indicated up-regulation of Atg3, Atg7 and Becn1 during the progression of EAM. Spatial transcriptomics analysis identified 5911 spots under the tissue and results showed an up-regulation of Atg3, Atg7, Becn1 and Map1lc3b in the hearts during the inflammatory phase of EAM. This increased expression was found throughout the entire heart section (Fig. 1B). Moreover, we detected the presence of LC3B and Beclin-1 proteins specifically localized within the inflammatory compartment of inflamed hearts (d19). Conclusions: In the EAM model, acute inflammation in the heart is associated with activated autophagy. Targeting this autophagic response could potentially improve disease outcomes. Financed by the National Science Centre (Poland), grant 2019/35/B/NZ5/00551
Abstract 12570: Catheter Ablation Rates for Typical Atrial Flutter in Military Tactical Athletes
Authors: Matthew Tunzi, Kelvin Bush
Journal: Circulation (2023)

Introduction: Cavotricuspid isthmus (CTI)-dependent atrial flutter is known to adversely impact exercise physiology and occupational readiness in active-duty military personnel. Despite guideline recommendations supporting catheter ablation for CTI-dependent flutter, there is a paucity of literature reporting the utilization and outcomes of catheter ablation in military personnel and other tactical athletes. Aims: This study aims to characterize United States military personnel diagnosed with CTI-dependent flutter and investigate the rates of catheter ablation and personnel returning to tactical athletic occupations. Methods: Military personnel diagnosed with CTI-dependent flutter from 2016 to 2022 were analyzed. Baseline clinical characteristics and typical flutter management was reviewed. CTI-flutter diagnoses were confirmed by electrocardiogram and electrophysiology study with entrainment or activation mapping. Results: During the study dates 40 military members (mean age, 40.7±10.7 years; 98% male; mean BMI 28.3±4.2 kg/m 2 ; mean LVEF 58.3%±7.7) were diagnosed with typical flutter. 34/40 (85%) of service members diagnosed with typical flutter were retained on military status after diagnosis. Of those retained, 13/34 (38.2%) were able to complete deployments. Electrophysiology study and successful CTI ablation was performed in 27/40 (67.5%) of personnel with zero complications. 26/27 (96.3%) servicemembers who underwent CTI ablation maintained their tactical occupation whereas only 8/13 (61.2%) service members who did not receive CTI ablation were retained (p=0.009). 10/27 (37.0%) who received CTI ablation were able to subsequently deploy whereas only 3/13 (23%) who did not receive CTI ablation were able to deploy (p=0.484). Conclusions: Most military tactical athletes with CTI-dependent flutter receive safe and effective CTI ablations. CTI ablation increases tactical occupation retention rates when compared to treatment without CTI ablation. This data supports the use of CTI ablation as first-line treatment for military personnel and highlights the role of increasing ablation rates in other similar athletic populations.
Abstract 12588: A Hyperactive Heart: A Case of Adderall-Induced Cardiomyopathy
Authors: Christian J Rose, Max W Klein, Ali Hama Amin
Journal: Circulation (2023)

Introduction: Stimulants are commonly used in the treatment of attention deficit hyperactivity disorder (ADHD). Cardiomyopathy is a rare but serious potential side effect of long-term stimulant use, even when done so for therapeutic purposes. Case: We present a 56-year-old female with ADHD and long-term high dose Adderall use who presented for progressively worsening dyspnea over the course of 1 year. Labs were notable for peak hs-troponin 246ng/L and pro-BNP 6598pg/mL. On admission, echocardiogram was notable for reduced left ventricular (LV) ejection fraction (EF) of 20-25% with normal LV wall thickness and mild-moderate valvular disease. ECG showed sinus rhythm 97 bpm, bi-atrial enlargement, normal voltage and no evidence of conduction delay. A left heart catheterization demonstrated no evidence of coronary artery disease. Cardiac MRI at 1.5T was notable for LVEF 18%, severe LV dilation (EDV 189mL/m2), severe right ventricular (RV) dilation (EDV 131mL/m2) with RVEF 26%, native T1 1099 msec, ECV 41%, normal T2*, and a very thin circumferential subendocardial late gadolinium enhancement involving the apical and mid segments (6% of LV mass). TSH, Vitamin B1, and selenium levels were normal, and there was no evidence of tachyarrhythmia throughout her admission. She denied significant alcohol use, illicit substance use, or family history of cardiomyopathy. The absence of paraprotein gap and other stigmata lowered suspicion for amyloidosis. Due to the results of her workup, her Adderall was discontinued as this was thought to be the likely cause of her newly discovered cardiomyopathy. She was discharged home on GDMT with close follow up with advanced heart failure. Discussion: The association between long-term stimulant use and cardiomyopathy is known, but not well described. Common cardiac effects of stimulants include tachycardia, hypertension and increased risk of arrhythmias, all of which are associated with increased workload on the heart and therefore contribute to the development of cardiomyopathy. Although generally rare, long-term use of prescription stimulant medications can contribute to the development of cardiomyopathy and should therefore be used sparingly and for the shortest period possible when necessary for the treatment of ADHD.
Abstract 12564: Safety, Pharmacokinetics, and Lipid Lowering Effects of the Oral, Liver-Targeted Liver X Receptor (LXR) Inverse Agonist TLC-2716 in Healthy Volunteers
Authors: Edward J Gane, Ryan S Huss, Jane Sur, Steve Weng, Eisuke Murakami, Archana Vijayakumar, Brian J Kirby, G. Mani Subramanian, Robert P Myers
Journal: Circulation (2023)

Background: The liver X receptors are oxysterol-activated nuclear hormone receptors that regulate cholesterol homeostasis and de novo lipogenesis. TLC-2716 is an oral, liver-targeted inverse agonist of LXRα/β in development for severe hypertriglyceridemia (SHTG) and NASH. Methods: In this randomized, double-blind, placebo (PBO)-controlled Phase 1 study (NCT05483998), healthy subjects (n=8/2 TLC-2716 vs PBO/cohort) received single ascending doses (SAD) of TLC-2716 (0.5, 2, 6, 12, or 20 mg) or multiple ascending doses (MAD) QD for 14 days (0.5, 2, 6, or 12 mg) while fed or 6 mg fasted. Safety, PK, serum lipid parameters by NMR LipoProfile ® , and gene expression in PBMCs were evaluated. Results: The proportion of subjects with adverse events (AEs) was 60% with PBO and 13-50% with TLC-2716 in the SAD cohorts (n=50), and 40% and 13-88%, respectively, in the MAD cohorts (n=50). All AEs were mild except an unrelated, Grade 2 thrombophlebitis in a subject on TLC-2716 2 mg. TLC-2716 was rapidly absorbed (T max 2-4h) with a short steady-state half-life (T 1/2 ~1.5-2.5h) and low maximal plasma concentrations (C max &lt;7 ng/mL), consistent with rapid hepatic uptake. With fed dosing, TLC-2716 AUC and C max increased less than dose proportionally and were 25-50% lower on Day 14 vs Day 1. With fasted dosing, exposures were similar on Days 1 and 14 and ~3-fold higher than with fed dosing. Significant, dose-dependent reductions in serum triglycerides, total and LDL-C, total and small LDL particles, and TG/HDL-C ratio—but not HDL-C—were observed with TLC-2716 ( Figure ). Lipid reductions were greatest in subjects with higher baseline values. TLC-2716 did not impact LXR target gene expression (e.g., reverse cholesterol transporters ABCA1 , ABCG1 ) in PBMCs, supporting its liver-targeted profile. Conclusion: The liver-targeted LXR inverse agonist TLC-2716 was well tolerated and caused significant lipid lowering in healthy subjects, supporting its evaluation in patients with SHTG and NASH.
Abstract 19132: Covid-19 Incidence, Mortality, and Disparities for Cancer, Cardio-Oncology, and The General Population: Machine Learning National Analysis of 27 Million Hospitalizations in 2020
Authors: Leslie Ynalvez, Dominique Monlezum, Abdelrahman Ali, Husam Shadid, Zachary Seal, Bala Pushparaji, Efstratios Koutroumpakis, Jong Kun K Park, Mehmet Cilingiroglu, Konstantinos Marmagkiolis, Cezar Iliescu
Journal: Circulation (2023)

Introduction: The paucity of large, longitudinal COVID data for higher risk cancer and cardio-oncology patients limits sufficient preparedness for the next pandemic. Therefore, questions regarding the incidence, outcomes, and disparities for the above patients need to be studied. Methods: BAyesian Machine learning-augmented Propensity Score translational (BAM-PS) statistics with multivariable regression was performed on the largest all payor US inpatient dataset, the National Inpatient Sample. Results: Of the 27,667,386 adult hospitalizations in 2020, 47,820 (0.17%) had COVID, of whom 2,430 (5.08%) had active cancer and 765 (1.60%) had cardio-oncology disease. In 2020, COVID was significantly less likely in patients with versus without active cancer (0.12% versus 0.18%, p&lt;0.001), with the most common malignancies in COVID including leukemia (22.22%), multiple myeloma (14.20%), lung (13.79%), and non-Hodgkin lymphoma (11.93%). The odds of being treated inpatient for COVID was significantly reduced by active cancer (OR 0.66, 95%CI 0.60-0.73, p&lt;0.001). In active cancer, COVID significantly increased mortality (OR 2.02, 95%CI 1.52-2.68, p&lt;0.001), though within COVID, neither active cancer nor cardio-oncology disease significantly increased mortality. In active cancer with COVID, mortality was significantly increased for the East South Central region (OR 0.08, 95%CI 0.01-0.95, p=0.045) compared to the New England region, though there were no other disparities by race, insurance, income, or urban density (with no disparities in cardio-oncology). Conclusions: This large nationally representative machine learning analysis suggests that cancer patients with COVID were less likely to be treated inpatient despite increased mortality. Cardiovascular disease does not significantly contribute to the mortality of these already extremely frail and complex patients.
Abstract 19126: Discovery of TMEM65 as a Positive Regulator of Mitochondrial Calcium Efflux
Authors: Joanne F Garbincius, Oniel Salik, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Josh J Doolittle, Emma K Murray, Michael P Lazaropoulos, Dhanendra Tomar, John W Elrod
Journal: Circulation (2023)

Introduction: The balance between mitochondrial calcium ( m Ca 2+ ) uptake and efflux regulates ATP production, but if perturbed causes m Ca 2+ depletion and energy starvation or m Ca 2+ overload and cell death. Disrupted m Ca 2+ homeostasis is implicated in ischemia-reperfusion injury, heart failure, and neurodegeneration. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of m Ca 2+ efflux in excitable tissues, supporting NCLX as a promising therapeutic target to limit pathogenic m Ca 2+ overload in organs like the heart and brain. However, a critical barrier to translation is that little is known about the mechanisms controlling NCLX activity. Goals: We used proximity biotinylation screening to identify the NCLX interactome and proteins that may regulate NCLX function. We identified TMEM65, a mitochondrial inner membrane protein of unknown function, as an NCLX-proximal protein. Hypothesis: Null mutation of TMEM65 causes mitochondrial encephalomyopathy and phenocopies genetic NCLX disruption. Therefore, we hypothesized that TMEM65 modulates m Ca 2+ efflux through NCLX. Approach: Here, we used measurements of m Ca 2+ exchange in AC16 cardiomyocytes with TMEM65 overexpression (OE) or CRISPR/Cas9 genetic disruption of TMEM65 to test TMEM65’s effect on m Ca 2+ flux and its functional dependence on NCLX. We used AAV-mediated Tmem65 knockdown (KD) and TMEM65 OE in mice to assess the effects of gain- or loss of TMEM65 expression on cardiac function. Results: TMEM65 OE potently enhanced m Ca 2+ efflux in vitro , and NCLX inhibition with CGP-37157 mitigated this effect. Knockout of TMEM65 attenuated m Ca 2+ efflux. In vivo Tmem65 KD reduced left ventricular fractional shortening and reduced S293 phosphorylation of pyruvate dehydrogenase in the heart, indicative of increased m Ca 2+ loading. In vivo TMEM65 OE did not alter cardiac function. Conclusions: We conclude that TMEM65 has an essential function to promote m Ca 2+ efflux, likely via positive regulation of NCLX, and is critical to limiting deleterious m Ca 2+ overload in the intact heart. Ongoing work is defining the functional interactions between TMEM65 and NCLX, and establishing the utility of targeting TMEM65 to restore m Ca 2+ homeostasis in heart failure and other excitable tissue diseases.
Abstract 12512: Predictive Factors of Right Heart Catheterization to Diagnose Pulmonary Arterial Hypertension Using Least Absolute Shrinkage Selection Operator (LASSO) Regression
Authors: R J White, Rogier Klok, Julia Harley, Giorgio Castellano, Mark Small, Dario Vizza, Dominik Lautsch
Journal: Circulation (2023)

Introduction: Right Heart Catheterization (RHC) is the gold standard diagnostic test to confirm Pulmonary Arterial Hypertension (PAH). However, not all patients receive a RHC to confirm diagnosis. Hypothesis: This study analyzed a real-world PAH dataset to understand factors predictive of RHC being used to confirm diagnosis. Methods: Data were analyzed from the 2022 Adelphi PAH Disease Specific Programme™ containing physician-provided patient information for PAH patients in the US, France, Germany, Italy, Spain, UK and Japan. As our outcome (RHC at diagnosis) is binary, logistic regression was used behind LASSO for 113 covariates (predictors). LASSO regression inputs many covariates, only those associated with the outcome are presented. Each covariate is tested individually and against all others. In LASSO an odds ratio (OR) is generated. An OR &gt; 1 or more indicates a predictor is associated with a higher likelihood of RHC at diagnosis, an OR &lt; 1 indicates a lower likelihood. RHC at diagnosis was physician-confirmed from patient records. Results: A total of 529 PAH patients with complete data for all covariates were analyzed. Mean age was 55 and 51% were female. Overall, 75% received a RHC at diagnosis. Patient refusal (34%) and deemed unnecessary by managing physician due to other testing (29%) were the most frequently cited reasons for lack of RHC. Of the 113 initial predictors, 24 were considered important in predicting RHC ( Figure 1 ). The leading predictors for RHC at diagnosis were patients classified as functional class (FC) III, those experiencing symptoms of dyspnea, palpitations and cyanosis, and those diagnosed at an accredited expert pulmonary hypertension (PH) center. Conclusions: Results indicate that RHC is more likely to be used for patients presenting with a higher FC, key PAH symptoms and diagnosed at PH expert centers. Further emphasis should be placed on RHC at diagnosis particularly within non-specialist settings to help achieve accurate diagnosis.